Studies of the roles of the Hunk serine-threonine kinase and the c -Myc oncogene in mammary gland development and carcinogenesis

Abstract

Breast cancer is the most commonly diagnosed malignancy in women in the United States. Unfortunately, the current breast cancer related mortality rate remains comparable to the mortality rate of more than a decade ago. These facts highlight the need for a better understanding of the biological pathways that lead to breast cancer. This dissertation addresses the role of specific genes implicated in the regulation of mammary development and breast cancer. The novel, SNF1-related serine/threonine kinase, Hunk (Hormonally Upregulated Neu-Tumor Associated Kinase), has recently been identified and has been demonstrated to inhibit murine mammary epithelial proliferation and differentiation when overexpressed. To address further the role of Hunk in development, we generated mice that possess homozygous null mutations at the Hunk locus. These mice do not demonstrate overt developmental defects, and mammary gland development proceeds normally in Hunk-deficient mice. These results suggest that Hunk is dispensable for normal embryonic development as well as post-natal mammary development. We also investigated the role of Hunk in tumorigenesis in vivo . Loss of Hunk significantly affects mammary tumorigenesis in an oncogene-specific manner. Primary mammary tumorigenesis initiated by the neu oncogene is delayed in Hunk-deficient animals relative to their wild type counterparts, whereas secondary tumorigenesis is inhibited by loss of Hunk in c-myc initiated tumors. The decreased metastatic potential in c-myc-induced Hunk-deficient tumors correlates with reduced TGF-β activity. TGF-β signaling and c-myc activity have been shown to play opposing roles in mammary epithelial proliferation and differentiation. We present evidence that, in vivo, c-myc expression can inhibit mammary gland Tgfb1 expression directly. This effect is likely to be mediated at the level of transcription and may involve the zinc-finger protein Miz-1. c-Myc-mediated inhibition of Tgfb1 expression, as well as the expression of other TGF-β target genes, occurs in a developmental stage-specific manner